Human γδ T cells induce CD8+ T cell antitumor responses via antigen-presenting effect through HSP90-MyD88-mediated activation of JNK

Abstract Background Human Vγ9Vδ2 T cells have attracted considerable attention as novel alternative antigen-presenting cells (APCs) with the potential to replace dendritic cells in antitumor immunotherapy owing to their high proliferative capacity and low cost. We seek to evaluate the effect of antigen-presenting γδ T cells (γδ T-APCs) in priming tumor-specific immune responses and clarify the mechanism by which γδ T cells develop antigen-presenting features. Methods The effect of γδ T-APCs in inducing antitumor responses of CD8+ T cells against osteosarcoma cells were tested both in vitro and in vivo. The mechanism by which γδ T cells develop APC features were further explored. Results Human γδ T cells stimulated by zoledronate markedly upregulated APC-related markers and effectively activated CD8+ T cells via cross-presentation of tumor antigen. γδ T-APCs were found to induce robust CD8+ T cell responses against osteosarcoma cells in vitro. In xenograft animal models, γδ T-APCs significantly suppressed osteosarcoma growth by priming CD8+ T cells. Mechanistically, activated γδ T cells produced increased HSP90 and fed back to upregulate MyD88, followed by JNK activation and subsequent improved CCL5 secretion, leading to enhanced CD8+ T cell cross-priming. Conclusions This study demonstrates the effect and mechanism of γδ T-APC-mediated cross-presentation in inducing the antitumor responses of CD8+ T cells. Our data suggest Vγ9Vδ2 T cells represent a promising alternative APC for the development of γδ T cell-based tumor immunotherapy.